CN109475510A - The extended release dosage form of Pregabalin - Google Patents

The extended release dosage form of Pregabalin Download PDF

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Publication number
CN109475510A
CN109475510A CN201780044181.XA CN201780044181A CN109475510A CN 109475510 A CN109475510 A CN 109475510A CN 201780044181 A CN201780044181 A CN 201780044181A CN 109475510 A CN109475510 A CN 109475510A
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Prior art keywords
component
composition
pregabalin
release
pearl
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Granted
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CN201780044181.XA
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Chinese (zh)
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CN109475510B (en
Inventor
约拉姆·塞拉
塞·鲁比诺夫
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Mapi Pharma Ltd
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Nhwa Pharmaceutical Corp
Mapi Pharma Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Abstract

The present invention relates to the extended release pharmaceutical composition comprising Pregabalin or its salt, it is suitable for discharging Pregabalin active constituent according to dual release overview.Preparation includes two kinds of components, the first (quick ER) provides the extended release of the active constituent continued from about 4 hours to about 6 hour with short control mode, and second (slow ER or maintenance) provides the extended release of the active constituent by 24 hours periods.After being administered orally to subject, the ratio of every kind of component in preparation be can be adjusted to realize desired AUC and therapeutic effect.The invention further relates to use method of the pharmaceutical composition for treating situation and disorder in response to Pregabalin treatment, the situation and disorder neuropathic pain for example relevant to diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), epilepsy, epileptic attack and fibromyalgia.

Description

The extended release dosage form of Pregabalin
Invention field
The present invention relates to the extended release dosage forms once a day of the Pregabalin with dual extended release overview, and Its purposes in the situation and disorder that treatment is treated in response to Pregabalin, the situation and disorder are for example all with diabetic keratopathy Enclose the relevant neuropathic pain of neuropathy (DPN), postherpetic neuralgia (PHN), epilepsy, epileptic attack (seizure) And fibromyalgia.
Background of invention
Pregabalin is the anticonvulsant drug for treating neuropathic pain and is used as partial seizures Complementary therapy and secondary generalization is with or without in adult.It also have been discovered that it is effective to generalized anxiety disorder sexual disorder, and This purposes is approved in European Union.It is typically considered to be the successor of Gabapentin.Pregabalin is by Pfizer with quotient The name of an articleTo release immediately hard-shell capsule sale comprising the newborn sugar and starch as non-active ingredient.Pregabalin is also For treating epilepsy, postherpetic neuralgia and diabetic peripheral neuropathy.Nearest research has been illustrated with Puri Bahrain is effective in terms of the chronic ache in the disorder for the treatment of such as fibromyalgia and spinal cord injury.Pregabalin is by beauty Drug of the first of Food and Drug Administration, state approval dedicated for treating fibromyalgia.Pregabalin with 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 225mg and 300mg capsule, and to include 20mg/mL Pregabalin and masking chemicals Bitter taste sweetener oral administration solution it is available.For the maximum of Pregabalin, recommended dose is daily in certain indications 600mg。
Currently, the principal indication and dosage about Pregabalin approval are: 1) management and diabetic peripheral neuropathy Become (DPN) relevant neuropathic pain, 100mg is 3 times a day (300mg)；2) postherpetic neuralgia (PHN), 75mg- 150mg 2 times a day or 50mg-100mg 3 times a day (maximum 300mg, it can increase to 600mg on other occasions)；3) As for the ictal epileptic attack in part adult complementary therapy (- 600mg/ days 150mg/ days, with 2-3 agent Amount is given)；With 4) manage fibromyalgia (- 450mg/ days 300mg/ days-with 2-3 dosage give).
The dosage regimen of current daily 2-3 dosage is due to significant compliance problem and due to releasing immediately agent The caused clinical side effects that steeply rise of drug blood plasma level are problematic after amount.In addition, the drug of fluctuation Plasma concentration can cause to apply the drug for being less than therapeutic dose in conservative dosage regimen, or in radical dosage regimen Apply the amount too big for specific patient.
As a result, it is desirable to develop dosage form once a day, presently commercially available immediate release formulation will be substituted.However, opening The dosage form once a day for sending out Pregabalin is challenging due to its unique absorption characteristic: Pregabalin is in small intestine and in colon Proximal region (caecum, colon ascendens) in absorb well.However, its absorption in distal colon (hepatic flexure of colon to rectum) is very Difference.This fundamental characteristics is considered as the major obstacle for developing the scheme once a day of this drug.
Several trials for developing the preparation once a day of Pregabalin are mentioned in the literature, most of to be based on gastric retentive oral dosage The exploitation of type, which attempts to extend residence time of the drug in the upper part of stomach and intestine (GI), in the stomach and intestine (GI) drug is preferably absorbed in upper part.
PCT International Patent Application WO 2005/041924 (corresponding to US 2005/0163848) is related to comprising Pregabalin With the compound (complex) of transport section such as alkyl sulfate.The compound particularly has in lower gastrointestinal tract in gastrointestinal tract There is the absorption of enhancing.The compound, and the composition and dosage form that are prepared using the compound, provide drug usually to 24 It is absorbed by the body in the period of hour, therefore it is said that can be realized the dosage form once a day for Pregabalin.
PCT International Patent Application WO 2006/078811 is related to pregabaline formulation, and it includes up to three kinds of components, including Immediate-release component, sustained-released component and sustained release component.Said preparation includes the soluble polymer that (a) is not depended on pH The active constituent such as Pregabalin of excipient coating；(b) activity of the insoluble polymer excipient coating of pH is not depended on Ingredient such as Pregabalin；(c) the active constituent such as Puri bar being coated by the soluble polymer excipient of pH dependence Woods.Said preparation is suitable for the discharge active component in three phases.In the first stage, active constituent rapidly discharges under one's belt；? Second stage, active constituent mainly pass through the sustained release time in stomach lower part, the duodenal segment of small intestine and jejunum part Section release；And in the phase III, the release of active constituent is merely deferred until jejunum part and the ileal segment of small intestine, wherein general Auspicious Bahrain is rapidly discharged.
PCT International Patent Application WO 2007/052125 is related to the medicine comprising Pregabalin, matrix formers and sweller Compositions, matrix formers include polyvinyl acetate and polyvinylpyrrolidone, and sweller includes crosslinked polyethylene Pyrrolidones, wherein pharmaceutical composition is suitable for administering orally once a day.
PCT International Patent Application WO 2009/066325 is related to controlled release drug composition, the controlled release drug group Closing object includes Pregabalin or its salt, hydrophobicity release control agent and optionally other pharmaceutically acceptable excipient.
PCT International Patent Application WO 2011/049309 (corresponding to US 2011/217374) discloses pharmaceutical composition, It includes the sustained release portion being coated on the surface with insoluble polymer and release immediately part, the sustained release portion Subpackage is containing the first active pharmaceutical ingredient, at least one selected from the group being made of insoluble polymer and hydrosoluble adhesive polymer Release the control substrate (base) and pharmaceutically acceptable carrier；The part that releases immediately includes the second active medicine Ingredient and pharmaceutically acceptable carrier.
PCT International Patent Application WO 2011/053003 teaches gastric retention extended release preparation, which persistently releases Putting preparation includes Pregabalin or its pharmaceutically acceptable salt, polyethylene oxide and polyvinyl alcohol-polyethylene glycol graft copolymerization Object, the swelling property and floatability of mesostroma are by using polyethylene oxide and polyvinyl alcohol-polyethyleneglycol-graft copolymer It improves, to control the release of drug.
United States Patent (USP) 7,731,989 is related to dosage form, the dosage form include dispersion in the polymer matrix in about 100mg to about Gabapentin between 4800mg, the polymer substrate include at least one swellable hydrophilic polymer, this is swellable Hydrophilic polymer be dimensionally swelling to certain size without restriction in water with promote dosage form under eating pattern Gastric retention in stomach, wherein after contact with water, Gabapentin by least 5 hours period by spread from dosage form come Release, and the Gabapentin of at least 40wt% is retained in dosage form for 1 hour after administration.
U.S. Patent application US 2002/0119197 is related to pharmaceutical dosage form, and it includes containing in control release composition The central core of drug agent, core tool there are two the opposed end surfaces of exposure and the core outer edge described two The periphery surface extended between opposed end surfaces, the periphery edge is surrounded by the sleeve of diffusion limitation, wherein the sleeve Limitation fluid is diffused into the core.
Chinese patent application CN 1857244 is related to slow release pregabalin composition, and it includes 50mg-1000mg's The Pregabalin of dose therapeutically effective or its drug salts and at least one rate of release control material.The composition is small at least 10 Up to discharging Pregabalin in 24 hours.
Indian patent application IN 2009DE01649 discloses extended release floating tablet, and it includes Pregabalins, gas Component, at least one rate control polymer and other drugs excipient are generated, wherein it is horizontal to provide treatment effective plasma level for tablet Pregabalin continue the period up to about for 24 hours.
Carry out several clinical tests currently to test the extended release dosage system of Pregabalin: 1) stage I and PK compare Preparation (dosage 82.5mg, 165mg, 330mg) is with twice daily (b.i.d) or three times a day once a day by Pregabalin ER (t.i.d) immediate release formulation given；2) phase II studies assessment is for treating the general comprising 165mg-498mg of fibromyalgia The preparation once a day of auspicious Bahrain；Include for treatment part epileptic attack and epilepsy with 3) stage III research assessment The preparation once a day of 82mg, 165mg and 330mg Pregabalin.
Currently, not ratifying the control delivery formulations of Pregabalin.Due to the unique absorption characteristic of Pregabalin, this is Unsatisfied medical need.
Summary of the invention
It is general according to dual extended release the present invention relates to the extended release pharmaceutical composition comprising Pregabalin or its salt Condition discharges Pregabalin active constituent.Composition of the invention is suitable for the unique release characteristics of Pregabalin, and includes two Kind of component, the first provides the extended release of the active constituent continued from about 4 hours to about 6 hour with short control mode, and And second provides the extended release of the active constituent by 24 hours periods.After being administered orally to subject, preparation In the ratio of every kind of component can be adjusted to realize desired AUC and therapeutic effect.In some embodiments, first group Point (being named as " quick ER " herein) be secondary part (that is, it constitute composition less than 50%), and the second component (being named as " slow ER " or " maintenance ") is major part (that is, its composition preparation is greater than 50%).In other embodiments In, the first component is major part (that is, its composition composition is greater than 50%), and the second component is secondary part (that is, its structure At preparation less than 50%).The invention further relates to use pharmaceutical composition to be used to treat the situation in response to Pregabalin treatment With the method for disorder, the situation and disorder neuropathic pain for example relevant to diabetic peripheral neuropathy (DPN), band Shape postherpetic neuralgia (PHN), epilepsy, epileptic attack and fibromyalgia.
Due to the absorption characteristic of Pregabalin after oral administration, it may be desirable to be configured to the compound to can be realized control Make the composition of release.Preparation of the invention provides the improved pharmacokinetics of active constituent, simultaneously because lower wave It moves index and minimizes side effect.The improved absorption that the present invention is based on Pregabalins in the upper part of stomach and intestine, and Its limited absorbent in the low portion of colon.The release mode of preparation of the invention is two-phase, and is suitable for Puri bar The unique release characteristics of woods, as a result, in some embodiments, a part of dosage is discharged in a manner of " quick ER " and remaining Dosage discharged in a manner of " slow ER ".Principle according to the present invention, preparation are released with two kinds of individual but parallel release overviews Put Pregabalin active constituent: a part of daily dosage is released with the short control mode for about -6 hours 4 hours (quick ER) It puts, and remaining daily dosage is provided with the 24 hours release modes (slow ER or maintaining component) controlled.Dosage form is preferably The control delivery formulations or extended release dosage system given and (preferably given after the meal and in sack time) once a day.
According on one side, the present invention provides oral extended release (ER) pharmaceutical composition, the oral extensions Discharging (ER) pharmaceutical composition includes as the Pregabalin of active constituent or its salt and pharmaceutically acceptable carrier or figuration Agent, wherein composition includes the period passed through about 4 hours to about 6 hours provide the release of Pregabalin active constituent first Second component of component and the release by providing Pregabalin active constituent in about 24 hours periods.Preferably, it combines Object is suitable for applying once a day.
In some embodiments, the first component (was released by quick or short extension in -6 hours 4 hours in each dosage Put) and the second component (the slow or longer extended release by 24 hours) between ratio at about 50%:50% (wt/wt) To between about 10%:90% (wt/wt), preferably from about 25%:75% (wt/wt) to about 10%:90% (wt/wt), such as About 15%:85% (wt/wt), about 30%:70% (wt/wt) or about 40%:60% (wt/wt).Every kind of possibility represents Ben Fa Bright individual embodiment.
In other embodiments, in each dosage the first component (the short extended release by -6 hours 4 hours) and Ratio between second component (the longer extended release by 24 hours) is in about 50%:50% (wt/wt) to about 90%: Between 10% (wt/wt), preferably from about 75%:25% (wt/wt) to about 90%:10% (wt/wt), for example, about 85%: 15% (wt/wt), about 70%:30% (wt/wt) or about 60%:40% (wt/wt).Every kind of possibility represents of the invention independent Embodiment.Composition of the invention is generally comprised from about 50mg to the Pregabalin of the total amount of about 600mg or its salt, wherein Accumulated dose separates between the first component and the second component.
In some embodiments, every kind in the first component and the second component is selected from comprising at least one each independently The pharmaceutically acceptable excipient for the group being made up of: polymer, adhesive, glidant, plasticizer, matrix are released the control Forming agent, disintegrating agent, lubricant and any combination thereof.
In some embodiments, the first component and/or the second component of preparation include at least one choosing each independently Free group consisting of releases the control polymer: hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), second Base cellulose (EC), cellulose acetate, acrylic polymer, polyvinylpyrrolidone (PVP), or combinations thereof.Currently preferably Release the control polymer be hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC) and A combination thereof.Every kind of possibility represents individual embodiment of the invention.
In other embodiments, adhesive is selected from by hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone (PVP) group At group.In other embodiments, lubricant is selected from and is made of magnesium stearate, Compritol 888 ATO and stearyl fumarate Group.In other embodiments, glidant is silica.
First component can be identical or different with the second component in composition.For example, every kind of component may include to appoint The identical or different polymer of what ratio.In some embodiments, the composition of two kinds of components is identical, but different using its Amount is to realize desired release overview.For the purpose of illustration, when using the extended release pearl being coated or micro tablet, phase Same coating can be used for both quick ER group and slow ER group, wherein the amount that every kind in each part is coated is different. Selectively, quick ER component can ER component can be in coating in the form of uncoated pearl or micro tablet, and slowly Pearl or micro tablet form.Every kind of possibility represents individual embodiment of the invention.In multiple embodiments, system Active constituent in every kind of component of agent is discharged with controlling release sequence, and it is suitable that the control release sequence is selected from the zero, first release Sequence, the second release sequence and third release sequence and its any virtual sequential.The release sequence of every kind of component can be with other groups Divide identical or different.Every kind of possibility represents individual embodiment of the invention.
In some embodiments, Pregabalin active constituent is discharged from pharmaceutical composition, to provide and substantially class Like dosage Pregabalin (such as) immediate release formulation compare lower Cmax, the smaller index of oscillation and/or Reduced side effect overview.
In some embodiments, composition of the invention is in be selected from ER pearl, micro tablet, bilayer tablet, glutoid glue The form of capsule or Perle, bead or combinations thereof.In some embodiments, composition of the invention is in ER pearl or miniature The form of tablet, the ER pearl or micro tablet are filled into hard gelatin capsule or Perle or are pressed into dispersible Tablet in.Also contemplate any of the above mixture.Every kind of possibility represents individual embodiment of the invention.
In a specific embodiment of composition of the invention, the first component and the second component be respectively in ER pearl or The form of micro tablet, the ER pearl or micro tablet are filled into hard gelatin capsule or Perle or are pressed into can In the tablet of dispersion.Every kind of component may include identical or different polymer in any proportion.In some embodiments, The composition of two kinds of components is identical, but using its different amount to realize desired release overview.For the purpose of illustration, when making When with the micro tablet of coating, identical coating can be used for both quick ER group and slow ER group, wherein each part In every kind of coating amount it is different.Selectively, quick ER component can in the form of uncoated micro tablet or ER pearl, and And slowly ER component can be in the form of the micro tablet of coating or ER pearl.Every kind of possibility represents individual implementation of the invention Scheme.
In some embodiments, the first component and the second component are respectively in the form of ER pearl or micro tablet, the ER Pearl or micro tablet include Pregabalin, first release the control polymer and at least one lubricant and/or matrix formers, In the first component be uncoated and wherein the second component also includes the coating for releasing the control polymer containing second, second releases Putting control polymer, can to release the control polymer with first identical or different.In specific embodiments, the first component and Second component respectively in the form of ER pearl or micro tablet, the ER pearl or micro tablet include Pregabalin, ethyl cellulose, Compritol 888 ATO and magnesium stearate, wherein the first component is uncoated and wherein the second component also includes containing ethyl fibre Tie up the coating of element.
In other embodiments, the first component and the second component are respectively in the form of ER pearl or micro tablet, comprising general Auspicious Bahrain, first release the control polymer, at least one lubricant and/or matrix formers and release the control containing second The coating of polymer, described second releases the control polymer, and can to release the control polymer with first identical or different, wherein phase Same coating is used for the first component and the second component in different amounts.In some embodiments, extended release agent of the invention Type passes through two kinds of optional technologies preparations: extruder and round as a ball, is then for example coated in Wurster column；Or in inertia sugar ball (NP) on, such as the multiple coatings in the fluidized bed for being equipped with Wurster.In some embodiments, ER pearl of the invention is logical It crosses in sugar ball higher slice or is prepared by squeezing out with round as a ball.In other embodiments, micro tablet or bilayer of the invention Tablet is prepared by granulation or direct pressing.Every kind of possibility represents individual embodiment of the invention.
Pharmaceutical composition of the invention is useful in the situation or disorder that treatment is treated in response to Pregabalin.Cause This, in a further embodiment, the present invention relates to by applying a effective amount of extended release of the invention as described herein Preparation come treat in response to Pregabalin treatment situation or disorder method.In other embodiments, the present invention relates to such as The extended release dosage system of invention described herein is used to treat the situation in response to Pregabalin treatment or the purposes of disorder.? In other embodiments, the present invention relates to extended release dosage systems of the invention as described herein for treating in response to Puri bar The situation of woods treatment or the purposes of disorder.
In some embodiments, epilepsy, pain, diabetic keratopathy are selected from response to the situation or disorder of Pregabalin treatment Peripheral neuropathy, postherpetic neuralgia, physiological status relevant to psychomotor stimulant, inflammation, gastrointestinal damage, wine Smart poisoning, insomnia, fibromyalgia, anxiety, depression, mania and two-phase disorder (bipolar disorder) and its any Combination.Every kind of possibility represents individual embodiment of the invention.
From detailed description given below, the other embodiments and full breadth of application of the invention will become bright It is aobvious.Although only passing through example however, it should be understood that detailed description and specific example indicate the preferred embodiments of the invention The mode of card provides, because a variety of change and modification within the spirit and scope of the present invention will be from the detailed description for ability Field technique personnel become obvious.
Brief description
Fig. 1 depicts Pregabalin extended release (ER) preparation (●) and Pregabalin according to the present invention and releases immediately (IR) (■) preparationOverview of the plasma concentration relative to the time.
External (◆) and (▲) release in vivo that Fig. 2 depicts Pregabalin extended release (ER) preparation according to the present invention Overview.
Detailed description of the invention
The present invention relates to the extended release dosage form once a day of novel Pregabalin and its treatment in response to Puri Purposes in the situation and disorder of Bahrain's treatment, the situation and disorder for example with diabetic peripheral neuropathy (DPN) phase Neuropathic pain, postherpetic neuralgia (PHN), epilepsy, epileptic attack and the fibromyalgia of pass.
Pregabalin as used herein is the pharmacological activity S- enantiomter of 3- amino methyl -5- methylhexanoic acid, It is the derivative of γ-aminobutyric acid (GABA).The structure of Pregabalin indicates below.
It is expected that any pharmaceutically acceptable form of Pregabalin, including but not limited to salt (such as HCl salt or alkali metal Salt), solvate (such as hydrate), homomorphs, polymorph, pseudopolymorph and prodrug, within the scope of the invention.
The present invention provides extended release dosage system, it is general to can be realized the active constituent for individually discharging overview according to two The control of auspicious Bahrain discharges: the first component of composition was discharged by -6 hours 4 hours periods, and the second component of preparation Provide " maintenance dose " of the Pregabalin active constituent by period release in up to 24 hours.In short, two kinds of components Provide the long-term continued treatment exposure to drug.The ratio of the first component and the second component in composition can be according to group Close object desired use and desired release overview and change.In some embodiments, component is under one's belt by first (quick ER) Release is until colon ascendens, and second (slow ER) component discharges in entire gastrointestinal tract.
Preparation
There is provided herein combination of oral medication, provide active constituent Pregabalin or the control of its salt according to two-phase overview System release, this every kind component discharge Pregabalin active constituent according to specific release overview.Oral extended release (ER) medicine Compositions include as the Pregabalin of active constituent or its salt, and wherein composition includes by about 4 hours to about 6 hours Period provides the first component of the release of Pregabalin active constituent and provided Pregabalin by about 24 hours periods Second component of the release of active constituent.Preferably, composition is suitable for applying once a day.
In multiple embodiments, the active constituent in every kind of component of preparation is discharged with controlling release sequence, the control Release sequence processed is selected from the zero, first release sequence, the second release sequence and third release sequence and its any virtual sequential.Every kind The release sequence of component can be identical or different with other components.Every kind of possibility represents individual embodiment of the invention. It is expected that after application, pharmaceutical composition of the invention provides and the routine comprising substantially the same dosage in the circulation of subject Immediate release dosage form compares lower CmaxThe index of oscillation of value and/or smaller active constituent, therefore lead to the secondary work reduced With.
In some embodiments, composition of the invention is in be selected from ER pearl, micro tablet, bilayer tablet, glutoid glue The form of capsule or Perle, bead or combinations thereof.ER pearl and micro tablet are currently preferred embodiments.In some realities It applies in scheme, in the form of ER pearl or micro tablet, the ER pearl or micro tablet are filled into hard bright composition of the invention In glue capsule or Perle or it is pressed into dispersible tablet.Also contemplate any of the above mixture.Every kind Possibility represents individual embodiment of the invention.
As used herein, term " control release " (CR) refers to the type of oral dosage form composition and release mode, Wherein active constituent Pregabalin or its salt are discharged by certain period of time or gradually at predetermined intervals.According to this hair Bright principle, term CR also cover sustained release (SR) preparation or extended release (ER) preparation of Pregabalin or its salt.
According to an embodiment, ER pharmaceutical composition of the invention includes the first component containing at least one polymer (quick ER component), first component allow active constituent to discharge by -6 hours about 4 hours short control section release times. Preferably, such polymer is selected from the group being made up of: hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC), cellulose acetate, acrylic polymer (including acrylate copolymer, acrylic ester polymerization Object etc.), polyvinylpyrrolidone (PVP), or combinations thereof.In a currently preferred embodiment, first (quick ER) group Polymer in point is hydroxypropyl cellulose (HPC).In another currently preferred embodiment, first (quick ER) component In polymer be hydroxypropyl methyl cellulose (HPMC), such as hydroxypropyl methylcellulose.In another currently preferred embodiment party In case, the polymer in first (quick ER) component is ethyl cellulose (EC), such asEC dispersion or EthocelTM。
Other examples of suitable polymer include but is not limited to that polyvinyl alcohol, polyethylene oxide, the vinyl of hydrolysis are poly- Close object, dextran, guar gum, pectin, starch, cellulosic polymer and any combination thereof.Every kind of possibility represents the present invention Individual embodiment.Acrylic polymer includes but is not limited to be referred to as the polymer of " carbomer " (for example, coming from B.F.Goodrich's) and934.Polyethylene oxide includes but is not limited to SentryWater-soluble resin DOW.Polyacrylate includes(can get from Rohm).Cellulosic polymer packet It includes but is not limited to hydroxypropyl methyl cellulose (for example, from Dow Chemical company)；Hydroxy propyl cellulose Element (such as from Hercules's)；Hydroxypropylcelluloether ether；Ethyl cellulose；Methylcellulose, carboxymethyl are fine Tie up plain sodium and the like.Every kind of possibility represents individual embodiment of the invention.
Pharmaceutical composition of the invention also includes the second component (slow ER component) containing at least one polymer, this Two components allow active constituent to discharge by about 24 hours longer control section release times.The polymer choosing of slow ER component From the inventory of the polymer offer above for quick ER component.Polymer in second component can be with gathering in the first component It is identical or different to close object, wherein every kind of possibility represents individual embodiment of the invention.In a currently preferred implementation In scheme, the polymer in second (quick ER) component is hydroxypropyl cellulose (HPC).In another currently preferred embodiment party In case, the polymer in second (quick ER) component is hydroxypropyl methyl cellulose (HPMC).In another currently preferred reality It applies in scheme, the polymer in second (quick ER) component is ethyl cellulose (EC).In order to realize longer section release time, The polymer that releases the control of second component can be to use or polymer can be incorporated into the different amount of the first component Into the slow release coatings being applied in quick ER component.Selectively, slow ER release component and quick ER release Both components may include containing the coating of polymer is released the control, and is applied in different ratios wherein being coated to realize expectation Release overview.
First component can be identical or different with the second component in composition.For example, every kind of component may include to appoint The identical or different polymer of what ratio.In some embodiments, two kinds of components include identical polymer/other figurations Agent, but using its different amount to realize desired release overview.For the purpose of illustration, when the extended release using coating When pearl or micro tablet, identical polymer coating can be used for both quick ER group and slow ER group, wherein for every The amount of every kind of coating of kind component is different.In another illustrative example, when using extended release pearl or micro tablet, the One component can be uncoated composition, and the second component can be composition identical with the first component, also contain There is the coating for releasing the control polymer, the amount of coating can change according to desired release overview.
The invention further relates to composition once a day, wherein the AUC drug blood plasma level of Pregabalin substantially with for Routine releases immediately Pregabalin (such as with trade markThe Pregabalin of sale) equivalent accumulation daily dosage can obtain The AUC drug blood plasma level obtained is identical or equivalent.When the data point infinitely great from time zero to the time be healthy volunteer and/ Or single-dose Pregabalin in target patient group (with) afterwards concentration (level) of the Pregabalin in blood plasma when, The present invention can determine AUC by the integral of those data points.
Pharmaceutical composition of the invention can also include additive well known by persons skilled in the art.For example, composition is also It may include stabilizer, tonicity enhancing agent (tonicity enhancing agent), buffer substance, preservative, thickener (viscosity enhancing), matrix formers (being also named as matrix formers herein), filler, glidant, disintegrating agent, plasticising Agent, diluent, adhesive, emulsifier, lubricant, wetting agent, flavoring agent, colorant, complexing agent and other excipient are for example beautiful Rice starch, wheaten starch, rice starch, potato starch and the like, gelatin, bassora gum, Brazil wax, three stearic acid are sweet Grease, the excipient based on cellulose such as microcrystalline cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, first Base hydroxypropyl cellulose, hydroxypropyl cellulose and the like.Every kind of possibility represents individual embodiment of the invention.
Other excipient include enteric polymer and surfactant.Multiple material is used as enteric polymer, this The material of sample includes the mixing of number of polymers acid and polymeric acid and such as material of shellac, cetanol and cellulose acetate Object.Suitable surfactant is such as NaLS.
Suitable filler includes but is not limited to sugar, such as lactose, sucrose, mannitol or sorbierite, ethyl cellulose, micro- Crystalline cellulose, microcrystalline cellulose of silication and the like.Every kind of possibility represents individual embodiment of the invention.Suitably Glidant is such as colloidal silicon dioxide or talcum.
Suitable tonicity enhancing agent is selected from ionic agent and nonionics.For example, ionic compound includes but is not limited to alkali Metal halide or alkaline-earth halide, such as CaCl2, KBr, KCl, LiCl, NaI, NaBr or NaCl or boric acid. Nonionic tonicity enhancing agent is such as urea, glycerol, sorbierite, mannitol, propylene glycol or dextrose.Every kind of possibility represents this The individual embodiment of invention.
The example of preservative is quaternary ammonium salt, such as benzalkonium chloride, benzoxonium Chloride or Polymeric quaternary ammonium salts；Thiosalicylic acid Alkyl mercuric salt, such as thimerosal, phenylmercuric nitrate, phenylmercuric acetate or Phenylmercuric Borate；P-hydroxybenzoate (parabens), Such as methyl p-hydroxybenzoate or propylparaben；Alcohol, such as methaform, benzyl alcohol or phenyl second Alcohol；Guanidine derivatives, such as chlorhexidine or poly hexamethylene biguanide or sorbic acid.Every kind of possibility represents list of the invention Only embodiment.
Disintegrating agent includes but is not limited to crosslinked polyvinylpyrrolidone, crosslinking carboxylic acid methyl cellulose, calcium silicates, carboxymethyl Sodium starch, methylcellulose；Agar；Bentonite；Calcium carbonate；Polyoxyethylene sorbitan fatty acid ester, stearic acid list glycerol Ester, cornstarch, potato starch, silica, croscarmellose sodium, Crospovidone, guar gum, starch glycolate Sodium and lactose.Every kind of possibility represents individual embodiment of the invention.
Plasticizer include dibutyl sebacate, polyethylene glycol (such as polyethylene glycol 400,6000 or 8000), polypropylene glycol, Glycerol, sorbierite, maltitol, glucose, sucrose, lanolin, palmitinic acid, oleic acid, stearic acid, fatty acid metal salt, sweet Arrcostab (such as the lemon of oil lecithin, glycerin monostearate, propylene glycol monostearate, acetylated glycerides, citric acid Triethylenetetraminehexaacetic acid ester, tributyl citrate, citroflex A-4 or CitroflexA-2), phthalic acid ester (example Such as diethyl phthalate), wax, hydrogenated vegetable oil and its mixture.
Suitable diluent includes but is not limited to be dehydrated Dicalcium Phosphate, sugar, lactose, calcium phosphate, cellulose, kaolin, sweet Reveal alcohol, sodium chloride and dried starch.Every kind of possibility represents individual embodiment of the invention.
Suitable adhesive includes but is not limited to water, ethyl alcohol, polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC such as hydroxypropyl methylcellulose), starch, gelatin or sugar.Sugar includes sucrose, dextrose, molasses and lactose.Every kind of possibility Represent individual embodiment of the invention.Thickener (viscosity intensifier) such as polyvinyl alcohol (PVA) is also used as slowly A part of delivery systme.
Suitable lubricant includes but is not limited to stearic acid, polyethylene glycol, glycerol derivatives such as Compritol 888 ATO (its It is also used as adhesive or matrix formers works) or stearate, such as magnesium stearate or stearyl fumarate.Often Kind possibility represents individual embodiment of the invention.Suitable wetting agent includes but is not limited to glycerol, starch and the like.
Suitable buffer or buffer substance include but is not limited to acid buffer agent, such as short chain fatty acids, citric acid, second Acid, hydrochloric acid, sulfuric acid and fumaric acid；With ealkaline buffer such as tris, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and Magnesium hydroxide.Every kind of possibility represents individual embodiment of the invention.
Composition of the invention can also include taste mask layer (taste-masking layer).Suitable taste mask layer includes But it is not limited to comprising layer below: ethyl cellulose, polyvinyl acetate (PVA), cellulose acetate (CA), cellulose acetate butyrate Element (CAB), methacrylate copolymer, such as with those obtainable copolymers of trade name " EUDRAGIT " (such as type L, S, RL, RS and NE30D), and combinations thereof.Every kind of possibility represents individual embodiment of the invention.
The amount and type of the excipient of addition are required according to specific, and usually in composition by weight from about In the range of 0.0001% to about 90%.
In some embodiments, preparation also includes the subcoat for separating active medicine phase with functional outer coatings. The example of excipient for attached bag clothing is polyvinyl alcohol (PVA).
Within the scope of the invention be in ER pearl, micro tablet, bilayer tablet, hard gelatin capsule or Perle, The pharmaceutical composition of the form of bead or combinations thereof.In some embodiments, composition of the invention is in ER pearl or micro chip The form of agent, the ER pearl or micro tablet are filled into hard gelatin capsule or Perle or are pressed into dispersible In tablet.It is also contemplated that any of the above mixture.Every kind of possibility represents individual embodiment of the invention.According to this hair Bright principle, tablet form include but is not limited to bilayer tablet, which includes that two or more different are pressed Stratum granulosum together, wherein one, individual layer is located on another top, wherein each individually layer includes to be formulated At the active constituent discharged in an individual manner.In one embodiment, the present invention relates to tablets, active in the tablet Agent is present in two individual layers, i.e., in bilayer tablet, wherein the layer comprising agent can be separated by intermediate non-active layer.
In some embodiments, extended release dosage form of the invention passes through two kinds of optional technologies preparations: extruder and It is round as a ball, then for example it is coated in Wurster column；Or on inertia sugar ball (NP), such as in the fluidized bed for being equipped with Wurster Middle multiple coatings.Therefore, in some embodiments, ER pearl of the invention by sugar ball higher slice or by squeeze out and it is round as a ball To prepare.In other embodiments, micro tablet of the invention or bilayer tablet are prepared by granulation or direct pressing.Often Kind possibility represents individual embodiment of the invention.
Pharmaceutical composition of the invention can also include the active constituent of micropackaging.According to these embodiments, activity at The little particle of point Pregabalin is coated or film surrounds, with the particle being formed within the scope of several microns to several millimeters.
Composition of the invention can also be mixed and be filled into capsule or pouch, or is pressed by conventional method Dispersible tablet.
Pharmaceutical composition of the invention can also be manufactured using common process as known in the art.For example, solid group Closing object such as tablet by wet granulation, non-slurry pelletizing, direct pressing and can be prepared in a similar manner.Suitable preparation includes will Main active and drug excipient are mixed to form the solid preformulation composite comprising homogeneous mixture.When referring to these When pre-preparation composition is uniform, mean for active constituent to be evenly dispersed in entire composition, so that composition Equally effective unit dosage forms such as tablet, pill and capsule can be easily separated into.
Application and therapeutical uses
The present invention also provides composition of the invention is applied to mammal, the preferably method of the mankind.It is expected that this The composition of text description is applied by oral route, to provide the transmucosal or gastrointestinal absorption of Pregabalin.Desired dosage can Easily to be presented with single dosage or with the separated dosage of interval appropriate application, but preferably, composition of the invention It is prepared for being administered once a day.
The amount of composition to be administered depend on various factors, including treated subject's (age and gender), disease Severity, and can be determined by the judgement of prescriber.In certain embodiments, composition is in unit dose Type.Pharmaceutical composition of the invention may include the Pregabalin of any dosage, preferably in total from about 50mg to about 600mg's Pregabalin or its salt, wherein total amount separates between the first component of composition and the second component as desired.Of the invention Yet other aspects are related to composition, wherein Pregabalin about 600mg, 550mg in total, 500mg, 450mg, 400mg, The dosage of the preparation of the Pregabalin active constituent of 350mg, 300mg, 250mg, 200mg, 200mg, 150mg, 100mg or 50mg It is interior.
The dosage of Pregabalin separates between the first component and the second component of preparation according to any ratio.In some realities It applies in scheme, the first component includes most of Pregabalin active constituent, i.e., is greater than 50% Pregabalin in composition.
In some embodiments, in each dosage the first component (the quick extended release by -6 hours 4 hours) and Ratio between second component (the slow extended release by 24 hours) is in about 50%:50% (wt/wt) to about 90%:10% (wt/wt) between, preferably from about 75%:25% (wt/wt) to about 90%:10% (wt/wt), for example, about 85%:15% (wt/wt), about 70%:30% (wt/wt) or about 60%:40% (wt/wt).Every kind of possibility represents individual reality of the invention Apply scheme.Preferably, the first component include 50% or more Pregabalin active constituent, such as 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% total Pregabalin dosage.Preferably, the second component includes 50% or less Pregabalin active constituent, such as 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5% total Puri bar Woods dosage.Any combination of such ratio by the present invention cover.Every kind of possibility represents individual reality of the invention Apply scheme.
In other embodiments, in each dosage the first component (the quick extended release by -6 hours 4 hours) and Ratio between second component (the slow extended release by 24 hours) is in about 50%:50% (wt/wt) to about 10%:90% (wt/wt) between, preferably from about 25%:75% (wt/wt) to about 10%:90% (wt/wt), for example, about 15%:85% (wt/wt), about 30%:70% (wt/wt) or about 40%:60% (wt/wt).Every kind of possibility represents individual reality of the invention Apply scheme.Preferably, the first component include 50% or less Pregabalin active constituent, such as 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5% total Pregabalin dosage.Preferably, the second component includes 50% or more Pregabalin active constituent, such as 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% total Puri bar Woods dosage.Any combination of such ratio by the present invention cover.Every kind of possibility represents individual reality of the invention Apply scheme.In some embodiments, composition in the first component comprising from about 200mg to about 550mg Pregabalin and Include the Pregabalin from about 50mg to about 250mg in the second component.In other embodiments, composition is in the first component Comprising including the Pregabalin from about 50mg to about 150mg from about 200mg to about 400mg Pregabalin and in the second component. In other embodiments, composition includes about comprising about 250mg Pregabalin in the first component and in the second component 100mg Pregabalin.Every kind of possibility represents individual embodiment of the invention.
Pharmaceutical composition of the invention is useful in the situation or disorder that treatment is treated in response to Pregabalin.Cause This, in a further embodiment, the present invention relates to treated by applying extended release dosage system of the invention in response to Puri The method of the situation or disorder of Bahrain's treatment.In other embodiments, the present invention relates to extended release dosage system of the invention use In the purposes of situation or disorder that treatment is treated in response to Pregabalin.Within the scope of the invention be that pharmaceutical composition is used for The purposes for treating the patient's condition or disorder treated in response to Pregabalin.
In some embodiments, situation or disorder are selected from epilepsy, pain, diabetic peripheral neuropathy, band-like blister Neuralgia, physiological status relevant to psychomotor stimulant, inflammation, gastrointestinal damage, alcoholism, insomnia, fiber flesh after rash Bitterly, anxiety, depression, mania and two-phase disorder and any combination thereof.Every kind of possibility represents individual implementation of the invention Scheme.
The invention further relates to the compositions comprising Pregabalin or other active components, are made of for treating to be selected from epilepsy Group neurological disorders or damage, treat secondary to apoplexy, head/traumatic brain injury or perioperative or postoperative nerve surgery hand Art, multiple sclerosis or involuntary action tremble the epilepsy of (involuntary action tremor).The invention further relates to Composition comprising Pregabalin or other active components, for treating and neuropathic pain, myalgia and skeleton pain phase The chronic ache of pass, tardive dyskinesia or migraine, reflex sympathetic dystrophy syndrome (RSD) are [also referred to as multiple Polygamy regional pain syndrome (CRPS)] and fibromyalgia or muscle disorder.The invention further relates in treatment psychiatry Disorder is such as, but not limited to used in bipolar disease, terrified, anxiety, depression, alcoholism and manic behavior comprising Puri The composition of Bahrain.Preparation or composition can be also used for treatment, and in U.S. Patent No. 6,310,098, (it is incorporated by reference into Situation described in herein), and particularly in hot flash, fever, the climacteric of nausea and vomiting other related syndromes Hormone change.The invention further relates to the symptom for the treatment of postmenopausal women, the symptom is selected from by urge incontinence, vagina The group of dry and astringent and dry eye syndrome composition.
As used herein term " therapeutically effective amount " or " effective quantity " refer to being enough to be administered to compound by Examination person provides the amount of the compound of beneficial effect.Effective quantity according to the principles of the present invention can be by ordinary skill people Member determines, and can test on various models both in vitro and in vivo.
Term " treatment " as used herein refers to stopping or slowing down the progress of treated specified disease or disorder.Art Language " treatment " further includes the generation for reducing various symptoms relevant to the disease treated or disorder.
As used herein, term administering " refers to contacting subject with composition of the invention.Implement at one In scheme, the present invention, which covers, is applied to human experimenter for composition of the invention.
It is proposed following embodiment so as to more fully illustration certain embodiments of the present invention.However, these embodiments are exhausted It should not be construed as limited to wide scope of the invention.Those skilled in the art are easy to imagine that principle disclosed herein Many variants and modifications, are made without departing from the scope of the present invention.
Embodiment
Embodiment 1: Pregabalin bilayer tablet
Table 1: composition 1
First (quick ER) layer adds 100ml water, then high shear is made by mixing Pregabalin, KLUCEL and HPMC Grain continues 1 minute, dries and mills in 0.8mm sieve to prepare in a fluidized bed.
Second (slow ER) layer is usually prepared by mixing Pregabalin, HPMC and ethyl cellulose.50ml ethyl alcohol is added, with High shear granulator continues 1 minute afterwards, dries and mills in a fluidized bed in 0.8mm sieve.
By this two layers in Picola rotary pelleting machine it is compressed together, to provide desired bilayer tablet.
Embodiment 2:Pregabalin micro tablet
Table 2: composition 2
First (quick ER) layer is based on the matrix similar with the matrix for bilayer tablet, but in screening and 50mg After HPMC K4M, 50mg Klucel LF, 1mg Syloid 244 and the 250mg Pregabalin of 0.5mg magnesium stearate mixing It is pressed into several micro tablets with 2mm diameter, the micro tablet discharges Pregabalin in a manner of not depending on pH Continue 6 hours.
The micro tablet of second of type, slow layer include with 50mg HPMC K100M, 50mg Ethocel 20cp, The 100mg Pregabalin of 1mg Syloid 244 and the mixing of 0.5mg magnesium stearate, are pressed into the several of 2mm diameter In micro tablet, micro tablet discharges Pregabalin in a manner of not depending on pH and continues 24 hours.
Embodiment 3:Pregabalin extended release pearl
500g Pregabalin is mixed with 15g PVP K30.Mixture is dissolved in 2 liters of ethanol/water 50%:50% to mix In object.
Pregabalin mixture is sprayed in the 45/50 mesh sugar ball fluidized in the fluidized bed for being equipped with Wurster column.
HPMC 5cp is sprayed on Pregabalin layer, 2%w/w separating layer is provided.
The HPMC pearl being coated is divided into two subgroups:
1. quick ER pearl: by ethyl cellulose 20cp and 10%w/w dibutyl sebacate and as the 2% of plasticizer The mixture of Klucel LF mixing is coated the level of the 10%w/w total coated to the polymeric layer based on total pearl weight.
2. slow ER pearl: by ethyl cellulose 20cp and 10%w/w dibutyl sebacate and as the 2% of plasticizer The mixture of Klucel LF mixing is coated the level of the 25%w/w total coated to the polymeric layer based on total pearl weight.
The group of two pearls is mixed with the ratio of 75% quick pearl and 25% slow pearl, accumulated dose is from 100mg to 500mg In the range of.
Embodiment 4:Pregabalin extended release pearl
500g Pregabalin is mixed with 500g Avicel 101 (microcrystalline cellulose) and 20g HPMC 50cp.It will mixing Object is soaked with 0.8 liter of water.
HPMC 5cp is sprayed on Pregabalin mixture, 2%w/w separating layer is provided.
Then Pregabalin mixture is passed through into the extruder with 1mm sieve, it is then round as a ball and be equipped with Wurster column Fluidized bed in it is dry.
Dry Pregabalin pearl is divided into two sub-groups:
1. quick ER pearl: by ethyl cellulose 20cp and 10%w/w dibutyl sebacate and as the 2% of plasticizer The mixture of Klucel Lf mixing is coated in pearl up to the level of the 10%w/w total coated of the polymeric layer based on total pearl weight.
2. slow ER pearl: by ethyl cellulose 220cp and 10%w/w dibutyl sebacate and as the 2% of plasticizer The mixture of Klucel LF mixing is coated in pearl up to the level of the 25%w/w total coated of the polymeric layer based on total pearl weight.
The group of two pearls is mixed with the ratio of 85% quick pearl and 15% slow pearl, accumulated dose is from 50mg to 600mg In the range of.
Embodiment 5:Pregabalin micro tablet
Table 3: quick ER micro tablet preparation
Table 4: slow XR micro tablet preparation
Embodiment 6:Pregabalin micro tablet
Table 5: quick ER micro tablet preparation
Table 6: slow XR micro tablet preparation
Pregabalin micro tablet is prepared according to following technique: by Pregabalin and ethocel in Diosna mixer Middle mixing, is added as needed water.Wet granulated mixture is placed in fluidized bed dryer, and in~50 DEG C of dryings.It will Dry mixture is screened by 0.710mm sieve.Compritol 888 ATO and magnesium stearate are sequentially added in mixture, Then mixed in V- blender.The mixture of powders of acquisition is suppressed under about 4.5 tons of pressing pressure, is had with preparation The uncoated micro tablet (quick ER micro tablet) of 3mm diameter.
By a part of uncoated tablet with Surelease 19040 (10.0g): the solution of water (6.97g) is coated, and is caused The slow ER micro tablet of Pregabalin.
The weight of micro tablet for every kind of ratio is weighed, and is filled into gelatine capsule (size 00).It can be with Mankind's PK overview required for ratio between " quick " ER and " slow " ER micro tablet is adjusted to.In each dosage quickly Ratio between ER micro tablet and slow ER micro tablet is in about 50%:50% (wt/wt) to about 10%:90% (wt/wt) Between, more preferably 40%:60% to 30%:70%.
Embodiment 7: Pregabalin micro tablet
Table 7: quick ER micro tablet preparation
Table 8: slow ER micro tablet preparation
By Pregabalin, hydroxypropyl methylcellulose (MethocelTME50), hydroxypropyl methylcellulose (MethocelTME4M), hydroxyl Third methylcellulose (MethocelTMK15M), hydroxypropyl cellulose (Klucel LF) mixes in Diosna mixer, according to need Add water.Wet granulated mixture is placed onIn fluidized bed dryer, and in~50 DEG C of dryings.Dry mixture is led to 0.710mm sieve is crossed to screen.Magnesium stearate is sequentially added in mixture, is then mixed in V- blender.In gelatin Tabletting, coating and filling in capsule carry out as described in Example 6.
Embodiment 8Dog PK research
Object of this investigation be Pregabalin extended release (ER) capsule and Pregabalin more according to the present invention immediately Discharge the internal and external release overview of (IR) preparation.Preparation describes in table 9.
Table 9: Pregabalin ER and IR preparation
For discharging determination in vivo, the single oral administration of 300mg extended release capsule or immediate release capsule is given To dog, and 0,10min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 7h, 9h, 12h, 15h, 18h, for 24 hours, 30h and 48h/72h blood is collected from foreleg vein.The concentration of Pregabalin in blood by HPLC-MS come It determines.
According to following parameter, In Vitro Dissolution passes through HPLC used as the phosphate buffer pH 6.8 and acetonitrile of mobile phase To determine:
Sampling time: 1h；6h；9h；16h；For 24 hours
Sampling volume: 5mL
Chromatographic parameter:
Column Equisil BDS-C8,5 μm, 150mm x 4.6mm ID
Flow 1.0mL/min
Wavelength 200nm
Volume injected 20μL
Runing time 7 minutes
Oven temperature 30℃
As a result
Fig. 1 depicts Pregabalin extended release (ER) preparation (●) and Pregabalin according to the present invention and releases immediately (IR) overview of the plasma concentration of (■) preparation relative to the time.
For Pregabalin ER, TmaxIt is 17.07h, C for 7.83h, MRT (0-t)maxFor 17940.148 μ g/L, and blood It starches concentration and is higher than 10000 μ g/L in 18h.
For Pregabalin IR, TmaxFor 2.67h, MRT (0-t) is 12.32h, and CmaxFor 35789.67 μ g/L.
External (◆) and (▲) release in vivo that Fig. 2 depicts Pregabalin extended release (ER) preparation according to the present invention Overview.
Conclusion:
Rate of release of the extended release capsule according to the present invention in dog is metastable, and mean residence time Longer, the two shows good extended release effect.With conventional capsule (Immediate release formulation) it compares, the present invention Extended release capsule show lower Cmax, longer Tmax, more stable rate of release and much longer MRT, own These all indicate its significant extended release property.Pregabalin shows with external rate of release a degree of in vivo Similitude, this indicates good internal in vitro correlation.
Although illustration and having described certain embodiments of the present invention, it will be clear that the present invention is unlimited In the embodiments described herein.Many modifications, variation, modification, replacement and equivalent will be obvious to those skilled in the art , without departing from the spirit and scope of the present invention, as described in through the attached claims.

Claims (29)

1. a kind of oral extended release (ER) pharmaceutical composition, oral extended release (ER) pharmaceutical composition includes to make For the Pregabalin of active constituent or its salt and pharmaceutically acceptable carrier or excipient, wherein the composition includes to pass through About 4 hours to about 6 hours periods provided the first component of the release of Pregabalin active constituent and by about 24 hours Period provides the second component of the release of the Pregabalin active constituent.
2. composition as described in claim 1, wherein the ratio of first component and second component is from about 50%: 50% (wt/wt) to about 10%:90% (wt/wt).
3. composition as claimed in claim 2, wherein the ratio of first component and second component is about 30%:70% (wt/wt) or about 40%:60% (wt/wt).
4. composition as described in claim 1, wherein the ratio of first component and second component is from about 50%:50% (wt/wt) to about 90%:10% (wt/wt).
5. composition as claimed in claim 4, wherein the ratio of first component and second component is about 30%:70% (wt/wt) or about 40%:60% (wt/wt).
6. composition as described in claim 1, wherein the composition is suitable for applying once a day.
7. composition as described in claim 1, comprising in total from about 50mg to the Pregabalin of about 600mg or its salt, wherein The total amount separates between first component and second component of the composition.
8. composition as described in claim 1, wherein first component and second component include each independently to A kind of few pharmaceutically acceptable excipient selected from the group being made up of: release the control polymer, adhesive, glidant, Plasticizer, matrix formers, disintegrating agent, lubricant and any combination thereof.
9. composition as claimed in claim 8, wherein first component includes at least one selected from the group being made up of Release the control polymer: hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), ethyl cellulose (EC), cellulose acetate, acrylic polymer, and combinations thereof.
10. composition as claimed in claim 8, wherein second component includes at least one selected from the group being made up of Release the control polymer: hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), ethyl cellulose (EC), cellulose acetate, acrylic polymer, and combinations thereof.
11. the composition as described in claim 9 or 10, wherein the polymer that releases the control is selected from the group being made up of: Hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC) and any combination thereof.
12. composition as claimed in claim 8, wherein described adhesive is selected from by hydroxypropyl cellulose (HPC) and polyethylene The group of pyrrolidones (PVP) composition.
13. composition as claimed in claim 8, wherein the lubricant is selected from by magnesium stearate, Compritol 888 ATO and hard The group of aliphatic radical fumaric acid sodium composition.
14. composition as claimed in claim 8, wherein the glidant is silica.
15. composition as described in claim 1, wherein the Pregabalin in every kind of component is discharged with controlling release sequence, institute It states control release sequence and is selected from the zero, first release sequence, the second release sequence and third release sequence and its any virtual suitable Sequence.
16. composition as described in claim 1, wherein Pregabalin is discharged from described pharmaceutical composition, with offer and base The immediate release formulation of the Pregabalin of similar dosage compares lower C in sheetmax, the smaller index of oscillation and/or reduced pair Act on overview.
17. composition as described in claim 1, the composition is in ER pearl, micro tablet, bilayer tablet, hard gelatin capsule Or Perle, bead, or combinations thereof form.
18. composition as claimed in claim 17, wherein first component and second component are respectively in ER pearl or micro- The form of matrix agent, the ER pearl or micro tablet are filled into hard gelatin capsule or Perle or are pressed into and can divide In scattered tablet.
19. composition as claimed in claim 18, wherein the micro tablet of first component or the ER pearl are not Coating, and wherein the micro tablet of second component or the ER pearl are coatings.
20. composition as claimed in claim 18, wherein the micro tablet of first component and second component Or the ER pearl is individually to be coated, wherein identical coating is in different amounts for first component and second group described Point.
21. composition as claimed in claim 18, wherein first component and second component are respectively in ER pearl or micro- The form of matrix agent, the ER pearl or micro tablet release the control polymer and at least one lubrication comprising Pregabalin, first Agent and/or matrix formers, wherein first component is uncoated and wherein second component also includes containing Two release the control the coating of polymer, and described second releases the control polymer, and can to release the control polymer phase with described first same Or it is different.
22. composition as claimed in claim 21, wherein first component and second component are respectively in ER pearl or micro- The form of matrix agent, the ER pearl or micro tablet include Pregabalin, ethyl cellulose, Compritol 888 ATO and stearic acid Magnesium, wherein first component is uncoated and wherein second component also includes the coating containing ethyl cellulose.
23. composition as claimed in claim 18, wherein first component and second component are respectively in ER pearl or micro- The form of matrix agent, the ER pearl or micro tablet release the control polymer, at least one lubricant comprising Pregabalin, first And/or matrix formers and the coating for releasing the control polymer containing second, described second releases the control polymer can be with Described first to release the control polymer identical or different, wherein identical coating is used for first component and institute in different amounts State the second component.
24. composition as claimed in claim 17, wherein first component and second component are respectively in the shape of ER pearl Formula, wherein the ER pearl in sugar ball by being coated or being layered or by squeezing out and round as a ball preparing.
25. composition as claimed in claim 17, first component and second component are respectively in micro tablet or double The form of synusia agent, the micro tablet or bilayer tablet are prepared by granulation or direct pressing.
26. a kind of treat the method for situation or disorder treat in response to Pregabalin, the method includes to needs its by Examination person applies the step of a effective amount of oral extended release (ER) pharmaceutical composition as described in any one of claim 1 to 25 Suddenly.
27. method as claimed in claim 26, wherein the situation or disorder are selected from epilepsy, pain, Diabetic Peripheral mind Through in lesion, postherpetic neuralgia, physiological status relevant to psychomotor stimulant, inflammation, gastrointestinal damage, alcohol Poison, insomnia, fibromyalgia, anxiety, depression, mania and two-phase disorder.
28. oral extended release (ER) composition as described in any one of claim 1 to 25 is for treating in response to general The situation of auspicious Bahrain's treatment or the purposes of disorder.
29. purposes as claimed in claim 28, wherein the situation or disorder are selected from epilepsy, pain, Diabetic Peripheral mind Through in lesion, postherpetic neuralgia, physiological status relevant to psychomotor stimulant, inflammation, gastrointestinal damage, alcohol Poison, insomnia, fibromyalgia, anxiety, depression, mania and two-phase disorder.
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